The present invention relates to the preparation of keto heterocycle derivatives of amino acids that have utility in the preparation of biologically active substances. These derivatives may, for example, be incorporated in inhibitors of serine proteases such as thrombin, Factor Xa, and Factor VIIa. As such these inhibitors have utility in the treatment of diseases that result from abnormal coagulation. Typical pathologic conditions include, for example, venous and arterial thrombosis, atrial fibrillation, stroke, restenosis, and recurrent myocardial infarction. These compounds are useful for preventing or treating unstable angina, refractory angina, disseminated intravascular coagulation, and ocular build up of fibrin. Since thrombin has also been demonstrated to activate a number of different cell types, these compounds are useful for the treatment or prophylaxis of septic shock and other inflammatory responses such as acute or chronic atherosclerosis. The compounds also have utility in treating neoplasia/metastasis and neurodegenerative diseases such as Alzheimer's and Parkinson's disease.
Previously peptidyl keto heterocycles have been prepared by conversion of cyano hydrins to imino ethers derivatives and cyclisation with, for example, amino phenols to afford peptidyl-keto-benzoxazoles (Edwards P D, et al., J. Am. Chem. Soc., 114, 1854 (1992)). Alternatively addition of lithiated heterocycles to N,O-dimethyl amides of the amino acid valine has been shown to proceed in good chemical and optical yield (Edwards P D, et al., J. Med. Chem., 38, 76 (1995)). While the N,O-dimethyl amide of BOCNH-Arg(Mtr) has been used to prepare keto amides (Deng J, et al., Angew. Chem. Int. Ed. Engl., 33 (17),1729 (1994)), and in failed attempts to prepare arginals (Guichard G, et al., Pept. Res., 6, 121 (1993)) they have not previously found use in the preparation of keto heterocycle basic amino acid derivatives.